Novel Oral Therapy Effective for Patients With Heavily Pretreated Chronic GVHD

By Cameron Kelsall, /alert Contributor

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Belumosudil exhibited strong efficacy and a tolerable safety profile as a treatment for patients with heavily pretreated chronic graft-versus-host disease (GVHD), according to data presented at the 62nd ASH Annual Meeting and Exposition.

The oral, selective ROCK2 inhibitor provoked durable responses at both daily and twice-daily dose levels, results also showed.

Specifically designed for the treatment of patients with cGVHD, belumosudil displayed promising efficacy in a previous dose-finding study, with two-thirds of participants achieving a partial or complete response to treatment. The phase 2 ROCKstar clinical trial enrolled 132 patients (median age, 56 years; median time from cGVHD diagnosis, 29 months), all of whom received between two and five previous lines of treatment.

In addition, 67% of the patient population had severe cGHVD, with 52% having involvement of four or more organs. Nearly three-quarters (72%) had three or more previous treatment lines, and 73% were refractory to their most recent line of therapy.

The researchers assigned patients to belumosudil at 200 mg per day or 200 mg twice-daily (n = 66 for both), with treatment ongoing until clinically significant cGVHD progression. Overall response rate (ORR) served as the study’s primary endpoint, with duration of response (DOR), Lee symptom scale score, failure-free survival, and reduction of corticosteroid dose, serving as secondary endpoints.

Median follow-up at the time of reporting was 8 months. The ORR for patients treated at the daily dose was 73% (95% CI, 60-83), and the ORR for patients treated at the twice-daily dose was 74% (95% CI, 62-84). 

Among the 29% of patients previously treated with ruxolitinib, the ORRs for daily and twice-daily belumosudil were 65% (95% CI, 41-85) and 72% (95% CI, 47-90), respectively. For the 35% of patients previously treated with ibrutinib, the ORRs were 73% (95% CI, 50-89) and 71% (95% CI, 49-87), respectively.

“High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of [four or more] organs and a refractory response to prior line of treatment,” wrote the researchers. “The response rate was similar across all affected organs.”

The median DOR was not reached, with a median time to response of 4 weeks. Nearly half (49%) the responding patients sustained their response for 20 weeks or longer. 

Thirty-nine percent of patients on the daily dose and 33% on the twice-daily dose achieved a clinically meaningful improvement on consecutive Lee Symptom Scale tests, which were defined as a reduction in symptom burden of 7 points or greater. This benefit extended to nonresponding patients (17%) in addition to responding ones (43%).

The rate of failure-free survival at the 6-month interval was 77% (95% CI, 69-84). Eighteen percent of patients discontinued corticosteroid use, while 13% discontinued calcineurin inhibitors.

Treatment-related adverse events accounted for 10% of discontinuations. Other factors contributing to treatment cessation included cGVHD progression (12%) and progression of underlying disease (3%).

Adverse events seen in at least 20% of the population included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%).

Thirty-four percent of patients experienced at least one serious adverse event, and 23% of patients had at least one liver-related investigation. However, bilirubin increase was only observed in one patient.

Five patients died due to adverse events, including one potentially related to treatment, and three patients died of other causes during long-term follow-up.

The researchers observed no cases of cytomegalovirus infection or reactivation. “Further studies will evaluate its use earlier in disease management,” they concluded.

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